The Ly-6/uPAR superfamily of receptors and secreted proteins contains a carboxy-terminal consensus sequence motif CCXXXXCN (SEQ ID NO:1) and one or several repeats of the Ly-6/uPAR domain, which is defined by a distinct disulfide bonding pattern between eight or ten cysteine residues (See Ploug et al., J. Biol. Chem., 268, 17539–17546 (1993); Ploug and Ellis, FEBS Lett., 349, 163–168 (1994); Casey et al., Blood, 84, 1151–1156 (1994)).
The superfamily can be classified into two subfamilies on the basis of the presence or absence of a GPI-anchoring signal sequence (See Adermann et al., Protein Sci., 8, 810–819 (1999)). GPI-anchored Ly-6/uPAR receptor proteins include the retinoic acid-induced gene E (RIG-E, or human Ly-6E), the E48 antigen (human Ly-6D); Ly-6H; the PSCA; CD59 or protectin; Lynx1 and uPAR (See Shan et al., J. Immununol., 160, 197–208 (1998); Brakenhoff et al., J. Cell Biol., 129, 1677–1689 (1995); Horie et al., Genomics, 53, 365–368 (1998); Reiter et al., Proc. Natl Acad. Sci. USA, 95, 1735–1740 (1998); Tone et al., J. Mol. Biol., 227, 971–976 (1992)). The E48 gene is known to be expressed in human keratinocytes, but not in lymphocytes, and it modulates desmosomal cell-cell adhesion of keratinocytes (Brakenhoff et al., J. Cell Biol., 129, 1677–1689 (1995); Schrijvers et al., Exp. Cell. Res., 196, 264–269 (1991)). The urokinase-type plasminogen activator receptor (uPAR) interacts in dynamic association with integrins and initiates signaling events that alter cell adhesion, migration, proliferation and differentiation (See Blasi and Carmeliet, Nat. Rev. Mol. Cell. Biol., 3, 932–943 (2002)). uPAR is a distant Ly-6/uPAR family member and, contrary to other members, it contains three contiguous copies of the Ly-6/uPAR domain. Differential cleavage of these domains regulates the multiple functions of uPAR (See Palfree, Immunol. Today, 12, 170 (1991); Montuori, et al., J. Biol. Chem., 277, 46932–46939 (2002)).
The second subfamily, which has a Ly-6/uPAR domain but no GPI-anchoring signal sequence includes SLURP-1 and SLURP-2 (See Adermann et al., Protein Sci., 8, 810–819 (1999); Tsuji et al., Genomics, 81, 26–33 (2003)). Mutations in the gene encoding SLURP-1 have been implicated in Mal de Meleda (MdM), as the MdM gene is located in a cluster of Ly-6 genes on chromosome 8q24.3 (See Fischer et al., Eur. J. Hum. Genet., 6, 542–547 (1998); Fischer et al., Hum. Mol. Genet., 10, 875–880 (2001); Eckl et al, Hum. Genet., 112, 50–56 (2003); Ward et al., J. Invest. Dermatol., 120, 96–98 (2003)).